Biology:TRAF6
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Short description: Protein-coding gene in the species Homo sapiens
 Generic protein structure example |
TRAF6 is a TRAF human protein.
Function
The protein encoded by this gene is a member of the TNF receptor associated factor (TRAF) protein family. TRAF proteins are associated with, and mediate signal transduction from members of the TNF receptor superfamily. This protein mediates the signaling not only from the members of the TNF receptor superfamily, but also from the members of the Toll/IL-1 family. Signals from receptors such as CD40, TNFSF11/TRANCE/RANKL and IL-1 have been shown to be mediated by this protein. This protein also interacts with various protein kinases including IRAK1/IRAK, SRC and PKCzeta, which provides a link between distinct signaling pathways. This protein functions as a signal transducer in the NF-kappaB pathway that activates IkappaB kinase (IKK) in response to proinflammatory cytokines. The interaction of this protein with UBE2N/UBC13, and UBE2V1/UEV1A, which are ubiquitin conjugating enzymes catalyzing the formation of polyubiquitin chains, has been found to be required for IKK activation by this protein. Two alternatively spliced transcript variants encoding identical proteins have been reported.[1]
Interactions
TRAF6 has been shown to interact with:
- ASK1,[2][3][4]
- CD40,[5][6]
- FHL2,[7]
- HSPB2,[8]
- IKBKG,[9][10]
- IRAK1,[11][12][13][14][15][16][17][18][19]
- IRAK2,[12][13]
- TAB1,[20][21][22]
- MAP3K7IP2,[9][19][20][21][23][24]
- MAP3K7[4][19][20][21][22][23][25]
- PPP4C,[26]
- RANK,[27][28][29][30][31]
- SDCBP,[11]
- SIGIRR,[32]
- Sequestosome 1,[33]
- TAX1BP1,[18]
- TNFAIP3,[34][35]
- TNFRSF13B,[36]
- UBE2N,[37] and
- Ubiquitin C.[10][24][26][38][39]
Model organisms
Model organisms have been used in the study of TRAF6 function. A conditional knockout mouse line called Traf6tm2a(EUCOMM)Wtsi was generated at the Wellcome Trust Sanger Institute.[40] Male and female animals underwent a standardized phenotypic screen[41] to determine the effects of deletion.[42][43][44][45] Additional screens performed: - In-depth immunological phenotyping[46]
| Characteristic | Phenotype |
|---|---|
| All data available at.[41][46] | |
| Peripheral blood leukocytes 6 Weeks | Normal |
| Insulin | Normal |
| Haematology 6 Weeks | Normal |
| Homozygous viability at P14 | Abnormal |
| Recessive lethal study | Abnormal |
| Body weight | Normal |
| Neurological assessment | Normal |
| Grip strength | Normal |
| Dysmorphology | Normal |
| Indirect calorimetry | Normal |
| Glucose tolerance test | Normal |
| Auditory brainstem response | Normal |
| DEXA | Normal |
| Radiography | Normal |
| Eye morphology | Normal |
| Clinical chemistry | Normal |
| Haematology 16 Weeks | Normal |
| Peripheral blood leukocytes 16 Weeks | Normal |
| Heart weight | Normal |
| Salmonella infection | Normal |
| Cytotoxic T Cell Function | Normal |
| Spleen Immunophenotyping | Normal |
| Mesenteric Lymph Node Immunophenotyping | Normal |
| Epidermal Immune Composition | Normal |
References
- ↑ "Entrez Gene: TRAF6 TNF receptor-associated factor 6". https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=7189.
- ↑ "ASK1 is essential for JNK/SAPK activation by TRAF2". Mol. Cell 2 (3): 389–95. September 1998. doi:10.1016/s1097-2765(00)80283-x. PMID 9774977.
- ↑ "Mediation of TNF receptor-associated factor effector functions by apoptosis signal-regulating kinase-1 (ASK1)". Oncogene 18 (42): 5814–20. October 1999. doi:10.1038/sj.onc.1202975. PMID 10523862.
- ↑ 4.0 4.1 "ASK1 inhibits interleukin-1-induced NF-kappa B activity through disruption of TRAF6-TAK1 interaction". J. Biol. Chem. 275 (42): 32747–52. October 2000. doi:10.1074/jbc.M003042200. PMID 10921914.
- ↑ "Two differently regulated nuclear factor kappaB activation pathways triggered by the cytoplasmic tail of CD40". Proc. Natl. Acad. Sci. U.S.A. 96 (4): 1234–9. February 1999. doi:10.1073/pnas.96.4.1234. PMID 9990007.
- ↑ "The c-IAP-1 and c-IAP-2 proteins are direct inhibitors of specific caspases". EMBO J. 16 (23): 6914–25. Dec 1997. doi:10.1093/emboj/16.23.6914. PMID 9384571.
- ↑ "Tumor necrosis factor receptor-associated factor 6 is an intranuclear transcriptional coactivator in osteoclasts". J. Biol. Chem. 283 (45): 30861–7. November 2008. doi:10.1074/jbc.M802525200. PMID 18768464.
- ↑ "HSP27 regulates IL-1 stimulated IKK activation through interacting with TRAF6 and affecting its ubiquitination". Cell. Signal. 21 (1): 143–50. January 2009. doi:10.1016/j.cellsig.2008.10.001. PMID 18950704.
- ↑ 9.0 9.1 "Interleukin-1 (IL-1) induces the Lys63-linked polyubiquitination of IL-1 receptor-associated kinase 1 to facilitate NEMO binding and the activation of IkappaBalpha kinase". Mol. Cell. Biol. 28 (5): 1783–91. March 2008. doi:10.1128/MCB.02380-06. PMID 18180283.
- ↑ 10.0 10.1 "The RING domain and first zinc finger of TRAF6 coordinate signaling by interleukin-1, lipopolysaccharide, and RANKL". J. Biol. Chem. 283 (36): 24871–80. September 2008. doi:10.1074/jbc.M802749200. PMID 18617513.
- ↑ 11.0 11.1 "Syntenin negatively regulates TRAF6-mediated IL-1R/TLR4 signaling". Cell. Signal. 20 (4): 666–74. April 2008. doi:10.1016/j.cellsig.2007.12.002. PMID 18234474.
- ↑ 12.0 12.1 "IRAK-M is a novel member of the Pelle/interleukin-1 receptor-associated kinase (IRAK) family". J. Biol. Chem. 274 (27): 19403–10. July 1999. doi:10.1074/jbc.274.27.19403. PMID 10383454.
- ↑ 13.0 13.1 "IRAK (Pelle) family member IRAK-2 and MyD88 as proximal mediators of IL-1 signaling". Science 278 (5343): 1612–5. November 1997. doi:10.1126/science.278.5343.1612. PMID 9374458.
- ↑ "IRAK-mediated translocation of TRAF6 and TAB2 in the interleukin-1-induced activation of NFkappa B". J. Biol. Chem. 276 (45): 41661–7. November 2001. doi:10.1074/jbc.M102262200. PMID 11518704.
- ↑ "TRAF6 is a signal transducer for interleukin-1". Nature 383 (6599): 443–6. October 1996. doi:10.1038/383443a0. PMID 8837778.
- ↑ "Identification of TIFA as an adapter protein that links tumor necrosis factor receptor-associated factor 6 (TRAF6) to interleukin-1 (IL-1) receptor-associated kinase-1 (IRAK-1) in IL-1 receptor signaling". J. Biol. Chem. 278 (14): 12144–50. April 2003. doi:10.1074/jbc.M300720200. PMID 12566447.
- ↑ "IRAK-4: a novel member of the IRAK family with the properties of an IRAK-kinase". Proc. Natl. Acad. Sci. U.S.A. 99 (8): 5567–72. April 2002. doi:10.1073/pnas.082100399. PMID 11960013.
- ↑ 18.0 18.1 "T6BP, a TRAF6-interacting protein involved in IL-1 signaling". Proc. Natl. Acad. Sci. U.S.A. 97 (17): 9567–72. August 2000. doi:10.1073/pnas.170279097. PMID 10920205.
- ↑ 19.0 19.1 19.2 "Interleukin-1 (IL-1) receptor-associated kinase leads to activation of TAK1 by inducing TAB2 translocation in the IL-1 signaling pathway". Mol. Cell. Biol. 21 (7): 2475–84. April 2001. doi:10.1128/MCB.21.7.2475-2484.2001. PMID 11259596.
- ↑ 20.0 20.1 20.2 "TAB2, a novel adaptor protein, mediates activation of TAK1 MAPKKK by linking TAK1 to TRAF6 in the IL-1 signal transduction pathway". Mol. Cell 5 (4): 649–58. April 2000. doi:10.1016/s1097-2765(00)80244-0. PMID 10882101.
- ↑ 21.0 21.1 21.2 Unutmaz, Derya, ed (2008). "TRAF6 autoubiquitination-independent activation of the NFkappaB and MAPK pathways in response to IL-1 and RANKL". PLOS ONE 3 (12): e4064. doi:10.1371/journal.pone.0004064. PMID 19112497.
- ↑ 22.0 22.1 "The kinase TAK1 can activate the NIK-I kappaB as well as the MAP kinase cascade in the IL-1 signalling pathway". Nature 398 (6724): 252–6. March 1999. doi:10.1038/18465. PMID 10094049.
- ↑ 23.0 23.1 "Role of the TAB2-related protein TAB3 in IL-1 and TNF signaling". EMBO J. 22 (23): 6277–88. Dec 2003. doi:10.1093/emboj/cdg605. PMID 14633987.
- ↑ 24.0 24.1 "NUMBL interacts with TAB2 and inhibits TNFalpha and IL-1beta-induced NF-kappaB activation". Cell. Signal. 20 (6): 1044–51. June 2008. doi:10.1016/j.cellsig.2008.01.015. PMID 18299187.
- ↑ "The type I TGF-beta receptor engages TRAF6 to activate TAK1 in a receptor kinase-independent manner". Nat. Cell Biol. 10 (10): 1199–207. October 2008. doi:10.1038/ncb1780. PMID 18758450.
- ↑ 26.0 26.1 "Protein phosphatase 4 negatively regulates LPS cascade by inhibiting ubiquitination of TRAF6". FEBS Lett. 582 (19): 2843–9. August 2008. doi:10.1016/j.febslet.2008.07.014. PMID 18634786.
- ↑ "Receptor activator of NF-kappaB ligand (RANKL) activates TAK1 mitogen-activated protein kinase kinase kinase through a signaling complex containing RANK, TAB2, and TRAF6". Mol. Cell. Biol. 22 (4): 992–1000. February 2002. doi:10.1128/mcb.22.4.992-1000.2002. PMID 11809792.
- ↑ "Characterization of the intracellular domain of receptor activator of NF-kappaB (RANK). Interaction with tumor necrosis factor receptor-associated factors and activation of NF-kappab and c-Jun N-terminal kinase". J. Biol. Chem. 273 (32): 20551–5. August 1998. doi:10.1074/jbc.273.32.20551. PMID 9685412.
- ↑ "Activation of NF-kappaB by RANK requires tumor necrosis factor receptor-associated factor (TRAF) 6 and NF-kappaB-inducing kinase. Identification of a novel TRAF6 interaction motif". J. Biol. Chem. 274 (12): 7724–31. March 1999. doi:10.1074/jbc.274.12.7724. PMID 10075662.
- ↑ "The involvement of multiple tumor necrosis factor receptor (TNFR)-associated factors in the signaling mechanisms of receptor activator of NF-kappaB, a member of the TNFR superfamily". J. Biol. Chem. 273 (51): 34120–7. Dec 1998. doi:10.1074/jbc.273.51.34120. PMID 9852070.
- ↑ "Receptor activator of NF-kappaB recruits multiple TRAF family adaptors and activates c-Jun N-terminal kinase". FEBS Lett. 443 (3): 297–302. January 1999. doi:10.1016/s0014-5793(98)01731-1. PMID 10025951.
- ↑ "SIGIRR, a negative regulator of Toll-like receptor-interleukin 1 receptor signaling". Nat. Immunol. 4 (9): 920–7. September 2003. doi:10.1038/ni968. PMID 12925853.
- ↑ "The atypical PKC-interacting protein p62 channels NF-kappaB activation by the IL-1-TRAF6 pathway". EMBO J. 19 (7): 1576–86. April 2000. doi:10.1093/emboj/19.7.1576. PMID 10747026.
- ↑ "The cytokine-inducible zinc finger protein A20 inhibits IL-1-induced NF-kappaB activation at the level of TRAF6". FEBS Lett. 442 (2–3): 147–50. January 1999. doi:10.1016/s0014-5793(98)01645-7. PMID 9928991.
- ↑ "Isolation and characterization of two novel A20-like proteins". Biochem. J. 357 (Pt 3): 617–23. August 2001. doi:10.1042/0264-6021:3570617. PMID 11463333.
- ↑ "TACI is a TRAF-interacting receptor for TALL-1, a tumor necrosis factor family member involved in B cell regulation". J. Exp. Med. 192 (1): 137–43. July 2000. doi:10.1084/jem.192.1.137. PMID 10880535.
- ↑ "Activation of the IkappaB kinase complex by TRAF6 requires a dimeric ubiquitin-conjugating enzyme complex and a unique polyubiquitin chain". Cell 103 (2): 351–61. October 2000. doi:10.1016/s0092-8674(00)00126-4. PMID 11057907.
- ↑ "Ubiquitin chain editing revealed by polyubiquitin linkage-specific antibodies". Cell 134 (4): 668–78. August 2008. doi:10.1016/j.cell.2008.07.039. PMID 18724939.
- ↑ "Lys63-linked polyubiquitination of IRAK-1 is required for interleukin-1 receptor- and toll-like receptor-mediated NF-kappaB activation". Mol. Cell. Biol. 28 (10): 3538–47. May 2008. doi:10.1128/MCB.02098-07. PMID 18347055.
- ↑ Gerdin AK (2010). "The Sanger Mouse Genetics Programme: high throughput characterisation of knockout mice". Acta Ophthalmologica 88: 925–7. doi:10.1111/j.1755-3768.2010.4142.x.
- ↑ 41.0 41.1 "International Mouse Phenotyping Consortium". http://www.mousephenotype.org/data/search?q=Traf6#fq=*:*&facet=gene.
- ↑ "A conditional knockout resource for the genome-wide study of mouse gene function". Nature 474 (7351): 337–42. Jun 2011. doi:10.1038/nature10163. PMID 21677750.
- ↑ "Mouse library set to be knockout". Nature 474 (7351): 262–3. Jun 2011. doi:10.1038/474262a. PMID 21677718.
- ↑ "A mouse for all reasons". Cell 128 (1): 9–13. Jan 2007. doi:10.1016/j.cell.2006.12.018. PMID 17218247.
- ↑ "Genome-wide generation and systematic phenotyping of knockout mice reveals new roles for many genes". Cell 154 (2): 452–64. 2013. doi:10.1016/j.cell.2013.06.022. PMID 23870131.
- ↑ 46.0 46.1 "Infection and Immunity Immunophenotyping (3i) Consortium". http://www.immunophenotyping.org/data/search?keys=Traf6&field_gene_construct_tid=All.
Further reading
- "The TNF-receptor-associated factor family: scaffold molecules for cytokine receptors, kinases and their regulators". Cell. Signal. 13 (6): 389–400. 2001. doi:10.1016/S0898-6568(01)00160-7. PMID 11384837.
- "TLR-independent anti-inflammatory function of intestinal epithelial TRAF6 signalling prevents DSS-induced colitis in mice". Gut 65 (6): 935–43. 2016. doi:10.1136/gutjnl-2014-308323. PMID 25761602.
- "Tumor necrosis factor receptor-associated factors (TRAFs)". Oncogene 20 (44): 6482–91. 2001. doi:10.1038/sj.onc.1204788. PMID 11607847.
- "Role of RANKL in physiological and pathological bone resorption and therapeutics targeting the RANKL-RANK signaling system". Immunol. Rev. 208: 30–49. 2006. doi:10.1111/j.0105-2896.2005.00327.x. PMID 16313339.
External links
- TRAF6 at the US National Library of Medicine Medical Subject Headings (MeSH)
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